Schizophrenia

Question 1

What is meant by psychosis?

Answer 1

Psychosis is a generic psychiatric term for a mental state often described as involving a ‘loss of contact with reality’. This could be present in other conditions as well. The ICD-10 classification of mental and behavioural disorders:

• ‘Psychotic’ simply indicates the presence of hallucinations, delusions, or a limited number of severe abnormalities of behaviour, such as gross excitement and overactivity, marked psychomotor retardation, and catatonic behaviour.

Question 2

What are the symptom domains and symptoms of Schizophrenia?

Answer 2

• Positive symptoms (Hallucinations, Delusions)
• Negative symptoms (Anhedonia, Asociality, Avoilition, Affective flattening)
• Disorganisation (formal thought disorder)
• Dysphoria and Depression
• Disturbed Behaviour (thought disturbance, anti-social behaviour, depressed behaviour)
• Impaired social cognition (emotional processing, theory of mind, social relationship perception)
• Neurocognitive functioning (attention, memory, excecutuve functioning).

Question 3

What symptoms of schizophrenia are primarily associated with disability and inability to work?

Answer 3

Negative symptoms (Aviolition, Asociality, Anhedonia and Affective flattening) and Neurocognitive effects (Attention, Memory and Excecutive functioning).

Question 4

What are the classical subtypes of schizophrenia?

Answer 4

The classical schizophrenia subtypes include:

• Paranoid - characterised by persecutory/grandiose delusions, derogatory auditory hallucinations.
• Hebephrenic (Disorganisation syndrome) - formal thought disorder, affective flattening/incongruity and bizarre behaviour.
• Catatonic - multiple motor, volitional and behavioural disorders, stupor and excitement.
• Simple - insidious but progressive impoverishment of mental life, without development of florid symptoms.

Subtyping is criticised as being temporally unstable, overlapping phenomenologically and of questionable validity and clinical relevance.

Question 5

Discuss the life expectancy of schizophrenic patients

Answer 5

Overall life expectancy is reduced by 20% for patients with schizophrenia. In fact their mortality is comparable to those who smoke heavily. Furthermore, this mortality gap between healthy and schizophrenics is widening, because of survival rates improving in the general population, more rapidly than those with schizophrenia. 60% of this excess in mortality is due to physical illness.

Question 6

What are the reasons for the excess mortality in Schizophrenia?

Answer 6

• People with schizophrenia tend to have physical illness diagnosed later with inadequate treatment by physicians.
• Diabetes and schizophrenia have intrinsic disease links. Metabolic syndrome is one of the most common factors underlying this increased mortality in schizophrenic patients.
• Schizophrenics are more likely to have a poor diet, less exercise, more likely to smoke, medications can cause metabolic side effects and weight gain (olanzapine) increasing the risk of cardiac disease and diabetes.
• Some of the increased mortality may be due to suicide.
• ?Antipsychotics cause weight gain and dyslipidemia leading to metabolic syndrome.

Question 7

Whar are other factors which contribute to the increased mortality and morbidity in people with SMI (Serious Mental Illness)

Answer 7

• Lack of access to and uptake of preventative care
• Suboptimal cardiac care (Mitchell & Lord - 2010)
• Physical illnesses underdiagnosed and undertreated ‘diagnostic shadowing’.
• Unhealthy lifestyle/physical inactivity
• Sleep and circadian disorders
• Social deprivation
• Poor diet: high in saturated fats and refined sugars, low in fruits and vegetables (Bly et al 2014)
• Poor compliance with medical treatment
• High levels of substance use (Olfson et al 2015)

Question 8

Describe the onset of Schizophrenia

Answer 8

Vague symptoms such as a change in personality, a decrease in academic, social and interpersonal functioning often begin in middle-late adolescence. Other prodromal symptoms include suspiciousness, sleep disturbance, paranoid notions and emotional withdrawal. These precede a visit to the psychiatrist by about 1-2 years.

• First psychotic episode usually occurs between the late teenage years and mid 30s.

Question 9

What is the sex disparity in Schizophrenia?

Answer 9

Affects males more than females 1.4:1. Men tend to present earlier, whereas more women present later on.

Question 10

List the aetiological/risk factors for Schizophrenia

Answer 10

• Genes
• Advancing paternal age
• Cannabis use
• Chronic social advsesity
• Obstetric brain insults

Question 11

Describe the influence of genetics to Schizophrenia development

Answer 11

Genetics is believed to play a role in the susceptibility to schizophrenia. The concordance for monozygotic twins is 48%, and for dizygotic twins is 12%. It is believed schizophrenia is highly polygenic, with a large heritable component but complex genetic architecture.

Question 12

How may advancing paternal age contribute to Schizophrenia risk?

Answer 12

Advancing paternal age is also an independent risk factor for schizophrenia. This may be due to the accumulation of de-novo mutations in the paternal sperm that contributes to the risk. (Sipos et al 2004).

Question 13

Describe the influence cannabis use may have on schizophrenia risk

Answer 13

• Heavy use at age 18 is associated with an increased risk of schizophrenia by six-fold.
• Cannabis use moderately increases risk of psychotic symptoms, but stronger in those predisposed.
• 40% increased risk of psychotic symptoms in anyone who has ever used cannabis.
• Findings were consistent with a dose-responsive effect.

Question 14

How may cannabis use interact with genes to influence schizophrenia risk?

Answer 14

Evidence overall does suggest an aspect of causality. Perhaps cannabis use causes schizophrenia in genetically susceptible individuals. A potential loci for this genetic-environment interaction may be at COMT.

• COM-T is located on chromosome 22q11. It encodes catechol-O-methyltransferase, an enzyme involved in the metabolism of dopamine in the synapse.
• A common mutation is valine –> methionine substitution, producing a less active enzyme.
• Homozygosity for valine confers increased risk of developing schizophreniform disorder but only after adolescent cannabis use.

Question 15

How do the aetiological factors produce the schizophrenia phenotype?

Answer 15

(neurodevelopmental hypothesis) Neurodevelopmental genes, neurotransmitter genes, environmental brain insults, substance use and chronic social adversity all contribute towards dopamine dysregulation which lead to the predisposition to developing psychosis.

This dopamine system dysregulation is reduced prefrontal dopamine activity coupled with increased mesolimbic dopamine transmission.

Question 16

Describe how migration data suggests the role of chronic social adversity as an aetiological factor for schizophrenia

Answer 16

• Afrocarribeans have much higher incidence of diagnosed Schizophrenia in the UK. In Germany it tends to be the Turkish. This is thought to be related to immigration, with the chronic social adversity of being a 2nd or 3rd generation immigrant possibly accounting for the increased diagnoses of schizophrenia.
  
  • First generation immigrants expect the social biases and xenophobia.
  • 2nd or 3rd generation may not deal with antisocial experiences as well because they believe they are home.

Question 17

What impact does the duration of the unreated psychosis (DUP) have?

Answer 17

The median time from onset of psychotic symptoms to treatment for psychosis is 1-2 years. This has an impact on patient outcomes:

• The longer the DUP, the poorer their response to treatment and poorer symptomatic and functional outcomes during the first several years of treatment (McGlashan et al 1996)

This may be due to:

• Antipsychotic medication slowing the active morbid process in the brain.
• Psychosocial effects of having an unchecked psychosis.

Question 18

Describe the negative symptoms of Schziophrenia

Answer 18

• Alogia - Decrease in verbal output or verbal expressiveness
• Affective blunting/flattening - Diminished facial, emotional expression, poor eye contact, decreased spontaneous movement, lack of spontaneity.
• Avolition - Subjective reduction in interests, desires and goals, and a behavioural reduction of self-initiated and purposeful acts
• Anhedonia - Inability to experience pleasure from positive stimuli
• Asociality - Lack of self-initiated social interactions

Question 19

What is the risk of suicide in schizophrenic patients, and what are the risk factors?

Answer 19

Schizophrenic patients are 12x more likely to commit suicide than the general population. This risk is particularly high in younger patients, with the risk decreasing over the decades however still remaining x4 more likely. Risk factors for suicide include:

• Male sex
• Young patients
• High level of education
• Fear of mental disintegration.
• Illness-related risk factors such as depression, active hallucinations, presence of insight.

Our only consistent protective factor is the delivery of and adherence to effective treatment.

Question 20

What are the types of positive symptoms experienced in schizophrenia?

Answer 20

Positive symptoms can be categorised into either:

Perceptual disorders:

• Hallucinations - can involve all senses.

Thought disorders:

• Disorder of the form of thought - Formal thought disorder
• Disorder of the stream of thought - Thought blocking
• Disorder of the control of thought - Thought insertion, withdrawal or broadcasting
• Disorder of the thought content - Delusions.

Question 21

Define halluication

Answer 21

A hallucination is the perception in the absence of an external sensory stimulus.

Question 22

Describe the nature of hallucinations in schizophrenia

Answer 22

Auditory is the most common form (40-80%), where people frequently hear voices and other sounds. It may be described as emanating from inside the head or a specific external location. Can also be in third person and may be a running commentary on what the person is doing. They can be thought echoes or even command hallucinations.

Visual hallucinations (15%) are often unformed such as glowing orbs, or flashes of colour.

Somatic/tactile hallucinations (5%) can include the feeling of being touched, of sexual intercourse or pain.

Olfactory and gustatory hallucinations are rare, but possible.

Question 23

Define delusion

Answer 23

A false, unshakeable belief which is out of keeping with the patient’s cultural and educational background.

Question 24

What are the common delusional themes in schizophrenia?

Answer 24

Common delusional themes: It is about them and their status in society and the way people are responding to them. Common delusions are:

• Grandiose: belief person has some special significance or power.
• Paranoid: belief one is being harmed or persecuted by particular person of group. Common and clinically important because they may prevent the individual from cooperating with evaluation or treatment.
• Nihilistic: uncommon, bizarre belief that one is dead or one’s body is breaking down or does not exist.
• Erotomanic: person erroneously believes that he/she has a special relationship with someone.

Question 25

What are the different ways thought disorders can present?

Answer 25

Disjointed, disconnected speech patterns reflect a disruption in the organization of a person's thoughts. Common presentations: * Tangentiality: moves away from the topic without appropriately answering a question. * Circumstantiality: answers to questions delayed by unnecessary details and irrelevant remarks. * Derailment: switches topic without any logic, 'knight's move thinking'. * Neologisms: creation of new idiosyncratic words. * Word salad: incoherence, words are thrown together without any sensible meaning.

Question 26

What are the clinical correlates of good and bad insight in schizophrenia?

Answer 26

Insight is acknowledging that you have a mental illness. It permits appropriate attribution of symptoms and often comes with acceptance of treatment. Patients also are aware of the consequences of their disorder. Insight has poor and good clinical correlates. Clinical correlates with poor insight: * Poor treatment outcome * Poor response to rehabilitation * Poor global insight/acceptance of need of treatment * Unawareness of social consequences Clinical correlates with good insight: * Medication adherence * Adherence to outpatient treatment * Fewer hospital admissions * Increased hopelessness, depression and suicidal behaviour.

Question 27

What are the outcomes of Schizophrenia?

Answer 27

* Regarded as lifetime illness with little hope of recovery. * 30-50% patients feature a fairly satisfactory outcome from a clinical and psychosocial point of view, with a consistent number achieving full recovery. Gaebel & Frommann 2000, Jobe and Harrow 2005, Lambert et al 2010, Warner 2009

Question 28

Describe the important antipsychotic drugs

Answer 28

First generation antipsychotics: * Chlorpromazine (low potency) * Loxapine (mid potency) * Haloperidol (high potency) Chlorpromazine was the first anti-psychotic medication. It is called a dirty drug because of it's actions on a large number of receptors. It is thought that the extra-dopaminergic effects were responsible to the side-effects. Second generation antipsychotics: * Clozapine * Olanzepine * Risperidone So-called 'atypicals'. They are less likely than haloperidol (the most widely and typically used antipsychotic) to cause extra-pyramidal symptoms (dyskinesia, akathisia, parkinsonism). Most antipsychotic medications have the same efficacy, however, clozapine turns out to be more effective than the rest. In patients with treatment refractory illness, clozapine can be useful. It is the only antipsychotic shown to be better than other antipsychotics. However, can cause agranulocytosis and so other drugs with a similar effect were attempted to be developed, such as olanzapine.

Question 29

Describe the dopamine hypothesis of schizophrenia

Answer 29

The dopamine hypothesis of schizophrenia is a model that attributes symptoms of schizophrenia (like psychoses) to a disturbed and hyperactive dopaminergic signal transduction (wiki). Overall, evidence suggests DA is overactive in the mesolimbic system producing positive symptoms, but may be underactive in the mesocortical system to produce negative symptoms of shcizophrenia.

Question 30

What evidence supports the dopamine hypothesis in Schizophrenia?

Answer 30

* Psychostimulant agents (such as amphetamine and cocaine) that trigger release of dopamine (DA) are associated with de novo psychosis. (Harris & Batki 2000) and worsening of psychotic symptoms in patients with partial remission. (Wolkin et al 1994) * L-DOPA aggravates the symptoms. Furthermore, Parkinson's patients given L-DOPA get hallucinations. * SPECT imaging reveals enhanced amphetamine-induced release of DA in schizophrenics compared with control. Suggesting presynaptic dopamine system abnormalities. * Evidence from postmortem and neuroimaging studies show a heightened synthesis of DA in people with schizophrenia (Seeman & Kapur 2000). * However, imaging evidence supports long-standing theory of insufficient dopamine in the prefrontal cortex - thought to be responsible for negative symptoms (Slifstein et al 2015) * Antipsychotics are dopamine antagonists and their clinical efficacy correlates with their receptor affinity at the D2 receptor. There is no such correlation for histamine or serotonin receptor blockade.

Question 31

What other neurochemical (non-dopamine) systems are implucated in the pathophysiology of Schizophrenia?

Answer 31

* Serotonin * Excitatory amino acids * Phospholipid membrane hypothesis

Question 32

Describe how serotonin may be implicated in schizophrenia pathology, including evidence.

Answer 32

Schizophrenia may be due to **excess** **serotonergic** activity * LSD and psilocybin (5HT receptor antagonists) cause positive symptoms in non-schizophrenics * Newer antipsychotics are potent 5HT receptor antagonists. Antagonism at the 5HT2 receptor causes reduction in psychotic symptoms * Some antipsychotics are both serotonin and dopamine antagonists (clozapine, risperidone, sertindole) and these have potent serotonin-related activities. Seems there is a clear role of serotonin in psychotic symptoms.

Question 33

Describe how excitatory amino acids may be implicated in schizophrenia pathology, including evidence.

Answer 33

* Insufficient excitatory amino acids or receptors (e.g. NMDA receptors) are implicated in schizophrenia * Low CSF glutamate, decreased glutamate receptors in the temporal lobes * Single dose of phencyclidine (non-competitive NMDA receptor antagonist) causes positive and negative symptoms in non-schizophrenics

Question 34

Describe the relationship between receptor occupancy and clinical effects of antipsychotics.

Answer 34

* Threshold for antipsychotic efficacy: \> 65% D2 receptor occupancy * \>78% threshold level occupancy for EPS, including akathisia * Applies to both FGAs and SGAs (First and Second Generation Antipsychotics).

Question 35

Describe the study looking into which antipsychotic to prescribe after first episode of psychosis

Answer 35

The CAFE study (Comparisons of Atypicals in First Episode psychosis) showed that: Efficacy and tolerability of Olanzapine, Quetiapine, and Risperidone in the treatment of early psychosis: A randomized, double-blind **52-week comparison**. It showed **similar effectiveness of all drugs tested in PANSS**. However, there are **differences in side effects**. * **Olanzapine** has a lot more **weight gain** than the other medications. You need to measure glucose, lipids, weight over time. * **Young patients** with early psychosis: **increased sensitivity to substantial weight gain** - more than half of weight gain took place during the first 12 weeks of antipsychotic treatment. * Treatment-emergent **metabolic** **syndrome** over 1-year FU in 13% of the total population (n=51) Individualizing antipsychotic treatment as well as targeting interventions to deal with weight gain and metabolic indices warranted from start of antipsychotic therapy.

Question 36

Describe the hypothesis linking increased dopamine in the mesolimbic pathway to psychosis.

Answer 36

Dopamine has a role in reward and reinforcement. It is involved in detecting new rewards in the environment. It enhances learning about these rewards and their associations. Increases in dopamine is linked to 'motivational salience' of environmental stimuli. It allows reward-associated stimuli to grab attention, and allows it to become the focus of goal-oriented behaviour. In schizophrenia, environmental/genetic predispositions cause a dysregulated firing and release of dopamine. This brings an aberrant sense of novelty and abnormal assignment of **salience** (importance) to **stimuli** and **internal** **representations**. These lead to delusions where a **cognitive** **scheme** is **developed** **to** **explain** **aberrant** **salient** **experience**. When this aberrant salience impacts on behaviour to causes distress, this leads to medical attention.

Question 37

Describe the use of antipsychotics in schizophrenia (prescription decision)

Answer 37

There is only modest efficacy differences between antipsychotics. Current prescribing choices largely based on: * Expected **side-effect profiles** * **Drug delivery options**, e.g. tablets, depot/long acting injection There is the perception that FGAs are typically associated with prominent movement and endocrine effects, while SCAs are commonly linked to metabolic and cardiovascular complications. However, with the notable exception of clozapine, large and influential trials such as CATIE, CUtLASS or EUFEst demonstrate that **both classes cause equally problematic side-effects**. Clozapine is reserved for treatment-resistent schizophrenia.

Question 38

Describe the Onset of Antipsychotic Efficacy

Answer 38

* A change in clinical symptoms can be appreciated shortly after starting antipsychotic medication. More improvement seen within the first 2 weeks than in any subsequent 2-week period, and the bulk of improvement over the first year occurs in the first month. (Agid et al 2003, 2006) * Early response is an indicator of continued responsiveness to treatment over at least 6 months.

Question 39

What causes relapses in schizophrenia?

Answer 39

Discontinuation of antipsychotic medication is associated with a 5-fold increase in risk of relapse over a 5-year follow-up period compared with maintenance therapy. (Robinson et al 1999). Abrupt discontinuation is associated with a greater (double) relapse rate than compared to gradual discontinuation. Some patients experience a breakthrough of psychotic symptoms even on medication - explained by the hypothesis of super-sensitive psychosis. This is the compensatory state of antipsychotic-induced upregulation of D2 receptors. It is potentially responsible for rebound psychosis, breakthrough of psychotic symptoms, medication tolerance and tardive dyskinesia.

Question 40

Describe the evidence for relapse prevention in schizophrenia

Answer 40

Systematic reviews looking at 65 studies up until 2010 found that antipsychotic drugs substantially reduce relapse risk in all patients with schizophrenia for up to 2 years of follow up. * 1-year relapse: 64% of those who discontinued, 27% with continuation. In the context of first-onset psychosis, a more recent systematic review looking at 6 studies found that: * 1-year relapse 77% of those who discontinued and 3% with continuation. This finding casts doubt on the statement in the literature that 20% of patients who have experienced a first episode of schizophrenia will not require antipsychotic treatment. (Zipursky et al 2014).

Question 41

Why Is Relapse Prevention Important?

Answer 41

* Frequent relapses might inhibit improvements in social performance after florid symptoms have been controlled by medication (Curson et al 1985). * Repeated psychotic episodes and prolonged periods of relapse are associated with impaired prognosis, poorer social function, worsening of symptoms, progressive cognitive deterioration, impaired functioning and reduced quality of life. * Prolonged periods of relapses are also associated with reduced responsiveness to antipsychotic medication (Emsley et al 2013). * There is also the risk of harm by patients to themselves and others. * Concern about the disruption of personal relationships as well as education or employment status. * Treatment refractoriness emerges in about 1 in 6 after relapse.

Question 42

Why are repeated relapses and psychotic episodes associated with worse outcomes and treatment refractoryness?

Answer 42

This may be because psychosis is neurotoxic. Neuroinflammation and oxidative stress leads to changes in the brain's neurochemical infrastructure and/or connectivity. Antipsychotic medication may be neuroprotective, curbing disease progression.

Question 43

What are the balancing concerns regarding continued antipsychotic therapy to prevent relapse?

Answer 43

* Possible loss of efficacy of medication * Concerns about the side effects of continuing antipsychotic medication.

Question 44

Describe the concerns of possible loss of efficacy of antipsychotic medication

Answer 44

* There is a statistically significant association between longer study duration and smaller relapse reduction by oral antipsychotic medication compared with placebo. (Leucht et al 2012). * May reflect dopamine D2/D3 receptor upregulation and resultant super-sensitivity * May simply reflect poorer medication adherence over time. * Patients with more chronic illness (duration \>10 years) have a greater risk of relapse, despite guaranteed medication deliver with depot/LAIs.

Question 45

What are the side-effects of antipsychotic drugs?

Answer 45

* Changes in brain structure in particular the parietal lobe and basal ganglia. * Metabolic side effects - metabolic syndrome in approximately one third of patients. (Mitchell et al 2013). * Weight-gain. 2013 review found that all 13 drugs were associated with increased weight gain compared to placebo. Especially olanzepine * Increased risk for coronary heart disease, cerebrovascular disease and congetive heart failure. (Correll et al 2017). * Direct cardiotoxic effects (Lee et al 2009, 2014). * Movement disorders (extrapyramidal symptoms) * Endocrine disorders such as hyperprolactinaemia

Question 46

What are the advantages of using depots/injections?

Answer 46

The advantages of using depots/LAIs are: * Avoid covert non-adherence allowing regular delivery of known dose. Also allows monitoring of missed or delayed appointments. Allows clinical to intervene with non-adherence, as a potential cause or sign of relapse. * Regular scrutiny of mental state and side effects. * Simplification of medication regimen makes the patient less likely to forget the dose and connect inadvertently overdose. * Clarifies poor adherence vs. poor response/treatment refractoriness * More predictable and stable serum drug level.

Question 47

What are the disadvantages of using depots/injections?

Answer 47

Disadvantages include: * Slow dose titration and longer time required to achieve a steady state. * Increase the risk of excess dosage particularly if oral antipsychotics are added. * Pain/discomfort at injection site.

Question 48

Discuss the evidence surrounding the benefits of depot/injection delivery of antipsychotics

Answer 48

While depot/LAI formulations displayed significant advantages in non-randomised observational studies, meta-analysis show there was no difference observed in RCTs. The mirror-image studies and cohort studies show benefits, but have weaknesses including lack of blinding, the fact that patients prescribed depot have more clinical contact, so potentially greater support etc., and indication bias (conscious choice of different treatments for patients with different prognosis, for example, depot/LAI preparations prescribed to more severely ill patients etc.). Traditional RCTs tend to show equivalence between depot and oral antipsychotic preparations. Data from Swedish databases on rehospitalisation and treatment failure for adult patients with schizophrenia (2006-2013) found that clozapine and depot/LAI antipsychotic medications are associated with the highest rates of prevention of relapse in schizophrenia, compared with no medication use. Further, risk of rehospitalisation about 20-30% lower during depot/LAI treatment compared to equivalent oral formulations.

Question 49

What are the steps and considerations you must take before prescribing clozapine?

Answer 49

1. No adequate response from two trials of antipsychotic medication. 2. Before assuming treatment-refractory illness ask: 1. Is diagnosis of schizophrenia correct 2. Are they treatment reluctant rather than treatment refractory? 3. Is the antipsychotic drug adequate in terms of dose, adherence, duration etc? 4. Are adverse effects masking a response 5. Presence of comorbid conditions 6. Contribution of substance use? 3. **Switch the medication or try a high-dose antipsychotic.** 4. **Combined antipsychotic use**.

Question 50

Discuss the evidence arround clozapine use as a antipsychotic

Answer 50

Systematic reviews and meta-analyses show that clozapine is superior for negative symptoms, total symptom score and proportion with clinical response in the short-term but not-sustained in the long-term. Other pragmatic studies: * PANSS total scores at 3 months had decreased more in those patients treated with clozapine than those treated with quetiapine or risperidone, but not olanzapine. (CATIE Phase 2 trial - McEvoy et al. 2006). * People with schizophrenia with poor treatment response to 2 or more antipsychotic drugs have an advantage in commencing clozapine rather than any other SGA in terms of symptom improvement over 1 year. (CUTLASS 2 - Lewis et al. 2006).

Question 51

What are the possible explanations for why there are sex differences in the age of onset and severity of multiple psychiatric illness, not just schizophrenia?

Answer 51

Possible explanations for this are: * Sexually dimorphic brain anatomy * Disproportionately high incidence of birth injury in boys * Differential effects of androgens and oestrogens * Buffering of early marriage in females

Question 52

What are the hormonal influences of schizophrenia developnent?

Answer 52

* There’s a focus on oestradiol in the literature. It seems that oestrogens are protective against psychosis. There is a correlation of fluctuating oestrogen levels (menstrual cycle) with severity of symptoms. * Antenatal vs postpartum psychosis is also different * Maybe this is because oestradiol has modulatory effects on neurotransmitter systems: Serotonergic – prepulse inhibition studies (PPI) is a neurological phenomenon in which a weaker pre-stimulus (prepulse) inhibits the reaction of an organism to a subsequent strong startling stimulus (pulse). This is a normal physiological phenomenon called prepulse inhibition. * **Prepulse inhibition is disrupted in schizophrenia** leads to the **sensorimotor gating deficiencies** occur in schizophrenics. * **Oestrogen is known to be protective against the disruption of prepulse inhibition**, due to it's **modulation of serotonergic pathways**. Testosterone is facilitatory to PPI disruption.

Question 53

What have GWAS studies on schizophrenia told us so far?

Answer 53

Common variants: * 1 **very strong effect** that is the **HLA** one, which was found to be associated in the 1970s through HLA mapping. But there are also loads of others that are above the genome wide threshold. If you increase the sample size, you would see even more that are ‘implicated’. This just means there are a lot of variants involved in schizophrenia - it is highly polygenic. * **DRD2** (the target of all effective antipsychotic drugs) and many genes (GRM3, GRIN2A, SRR, GRIA1) involved in the **glutamergic** **neurotransmission** and synaptic plasticity * In addition, associations at CACNA1C, CACNB2 and CACNA1I, which encode **voltage gated calcium channel subunit**s, extent previous findings implicating members of this family of proteins in schizophrenia and other psychiatric disorders.

Question 54

What rare variants contribute more significantly to the development of schizophrenia?

Answer 54

* **DISC1** - (Disrupted in Schizophrenic 1) a gene affected by a translocation that causes schizophrenia. However, it also causes various forms of mental illness in some carriers. Furthermore, this hasn’t been found in any other family studies. * **22q11 deletion syndrome** - a deletion that can cause a variety of symptoms including various forms of mental illness in some carriers. It is the most common single genetic cause of schizophrenia. Again though, it causes 'velo-cardio-facial' syndrome characterised by a range of other symptoms such as hypoparathyroidism, underdeveloped thymus or absent thymus, resulting in problems in the immune system, heart defects, cleft lip/palate. Even in these, it only increases risk of schizophrenia in 1/3 of patients. * Furthermore approximately 1% of patients with schizophrenia have 22q11 deletion syndrome, but many of them don’t have velocardiofacial syndrome; they only have schizophrenia * The schizophrenia in 22q11 DS is indistinguishable by symptoms, treatment response, neurocognitive profile or MRI brain abnormalities.